Lecture 13 Echinocandins and Terbinafine

Question 1

Give 3 examples of echinocandins

Answer 1

Caspofungin (oldest)
Micafungin
Anidulafungin (newest)

Question 2

What is the mode of action of echinocandins?

Answer 2

bind to the Fks1p subunit = blocks B1,3-D-glucan synthesis

Question 3

In what form are echinocandins given and why?

Answer 3

IV

Due to being a large molecule

Question 4

Which species do echinocandins work on?

Answer 4

candida

Aspergillus

Question 5

What is the licensed indication for caspofungin?

Answer 5

Invasive candidosis in adults
Aspergillosis as a refractory treatment i.e. must have tried another drug 1st
Empirical therapy for presumed fungal infection e.g. neutropenia, fever

Question 6

What is the licensed indication for anidulafungin?

Answer 6

invasive candida in adults

Question 7

What is the licensed indication for micafungin?

Answer 7

Invasive candidosis in children and adults
Oesophageal candidosis in adults
Prophylaxis against candidosis in adults or children e.g. for hematological diseases, bone marrow transplant, etc.

Question 8

Explain the licensing trial for caspofungin comparing caspofungin and amphotericin B

Answer 8

Compared caspofungin and amphotericin B in nonneutropenic patients with candidaemia
No significant difference between drugs in successful outcomes
Significantly less renal toxicity and hypokalaemia in amphotericin B patients

Question 9

Explain the licensing trial for caspofungin in use for refractory invasive aspergillosis

Answer 9

83 patients
Favorable outcome: 37 
Stable disease: 6
Failure of therapy: 40
Only 1 serious adverse event

Due to lack of comparison drug and small study size, 2nd line license given for this use

Question 10

Explain the licensing trial for anidulafungin

Answer 10

Comparison between anidulafungin and fluconazole (standard treatment for candidosis at the time) in nonneutropenic patients with invasive candidosis
No of patients: 235
Successful outcomes significantly higher for anidulafungin
Number of adverse events about the same

Question 11

Explain the licensing trial for micafungin

Answer 11

Compared micafungin and ambisome in patients with invasive candidosis
494 patients - half on each drug
The successful outcome of both drugs was similar
Less adverse effects with micafungin

Question 12

Where are the majority of micafungin metabolized?

Answer 12

Caspofungin: >90% in blood and tissues
Anidulafungin: >90% in blood
Micafungin: hepatic metabolism

Question 13

What are the toxicity risks associated with caspofungin?

Answer 13

Loss of potassium
Fever
Chills
Mildly deranged liver functions
Generally well tolerated

Question 14

What are the toxicity risks associated with anidulafungin?

Answer 14

headache
nausea
mildly deranged liver functions
Generally well tolerated

Question 15

What are the toxicity risks associated with micafungin?

Answer 15

Mildly deranged liver function
Headache
Generally well tolerated

Question 16

What drugs does caspofungin interact with?

Answer 16

some immunosuppressants
steroids - in children
some antivirals and antibiotic

Question 17

What drugs does anidulafungin interact with?

Answer 17

no known drug interactions

Question 18

What drugs does micafungin interact with?

Answer 18

some immunosuppressants

Question 19

Which species are and are not resistant to echinocandins and how?

Answer 19

resistance is rare
Candida albicans - resistance associated with mutations in the gene FSK1 gene of B 1-3 glucan synthase complex, particularly codon 645 Ser
C. glabrata - mutations in FSK1 and 2 genes associated with echinocandins resistance
Cryptococcus spp not susceptible - may be due to glucan synthase target alteration, efflux pumps or degradation pathways present

Question 20

Explain the paradoxical effect with echinocandins and how this occurs

Answer 20

Initially, as the dose increases the growth of C. albicans decreases - very large doses sees an increase in growth
The effect is strain specific and dependent on growth medium - Also seen in Aspergillus fumigatus
Possible mechanism theories:
Upregulation of chitin biosynthesis to counteract the reduced glucan production
Upregulation of cell wall integrity pathway (protein kinase C)

Question 21

Name the one drug in the allylamine class

Answer 21

Terbinafine

Question 22

What is the mode of action of terbinafine?

Answer 22

Inhibition of squalene epoxidase - function is to catalyze a step in the ergosterol synthetic pathway

Question 23

What form does terbinafine come in?

Answer 23

Tablets
gel
cream
spray

Question 24

What is terbinafine indicated for?

Answer 24

Dermatophyte infections of the skin and nail

Cream for skin infections due to yeast

Question 25

Explain the study proving the efficacy of terbinafine

Answer 25

Compared terbinafine and itraconazole pulse therapy (means it was given 1 week in every 4 weeks to reduce costs)
Terbinafine was statistically better at curing than itraconazole (includes clinical cure, mycological cure (inability to grow the fungus) and complete cure)

Question 26

How much of terbinafine is protein bound?

Answer 26

> 90%

Question 27

How is terbinafine metabolized?

Answer 27

extensively by CYP enzymes

Question 28

What is the half-life of terbinafine?

Answer 28

22h

Question 29

What is the dosing of terbinafine?

Answer 29

1 daily

Question 30

How is terbinafine eliminated?

Answer 30

80% in the urine

20% in the feces

Question 31

What are the adverse effects of terbinafine?

Answer 31

Occasionally liver dysfunction

Altered taste

Question 32

Which drugs interact with terbinafine?

Answer 32

Lots due to CYP metabolism

Some other antifungals, antidepressants, etc (similar to azoles)

Question 33

Explain how affected terbinafine is by resistance and how this comes about?

Answer 33

resistance is rare
Trichophyton rubrum has a high minimum inhibitory concentration to terbinafine
Mutations occur via substitutions in the squalene epoxidase gene